Adefovir dipivoxil, which is a useful antiviral drug, is a nucleotide reverse transcriptase inhibitor, which exhibits a marked in vivo antiviral activity against especially both HIV and Hepatitis type B virus (HBV). The adefovir dipivoxil has been sold on the market under the trademark “Hepsera.”
Adefovir dipivoxil can be prepared, for example, according to a method as described in U.S. Pat. No. 5,663,159. The document discloses the method for preparation of adefovir dipivoxil of Formula 1 comprising reacting adefovir of Formula 2 as a starting material with chloromethylpivalate at a temperature of 22° C. under the presence of dimethylformamide (DMF) and N,N′-dicyclohexyl-4-morpholine-carboxamidine to give a yield of 32% of adefovir dipivoxil.

However, the above method has a problem in that large quantities of byproducts are generated during the synthetic reaction, which results in a low yield of adefovir dipivoxil.
In order to solve the problem, Korean Patent No. 0700087 discloses a method of synthesizing adefovir dipivoxil of Formula 1 by allowing adefovir of Formula 2 as a starting material to react with chloromethylpivalate under the presence of 1-methyl-2-pyrrolidone (NMP) and triethylamine (TEA), which is represented by the following Reaction Scheme 2.

The above method shows the improvement in a yield of adefovir dipivoxil by approximately 55%, but there are still problems in that since its reaction temperature should be increased to 60° C. or higher, related compounds (impurities) are thus generated in abundance, and the amount of 1-methyl-2-pyrrolidone used in the reaction and byproducts of Formula 3 generated during the reaction accounts for about 15% or higher of final products, which makes it difficult to purify adefovir dipivoxil.
